The role of limbic-striato-pallidal circuitry in cocaine-induced reinstatement was evaluated. The transient inhibition of brain nuclei associated with motor systems [including the ventral tegmental area (VTA), dorsal prefrontal cortex (dPFC), core of the nucleus accumbens (NAcore), and ventral pallidum (VP)] prevented cocaine-induced reinstatement. However, only the VP proved to be necessary for food reinstatement, suggesting that the identified circuit is specific to drug-related reinstatement. Supporting the possibility that the VTA-dPFC-NAcore-VP is a series circuit mediating reinstatement, simultaneous unilateral microinjection of GABA agonists into the dPFC in one hemisphere and into the VP in the contralateral hemisphere abolished cocaine reinstatement. Although dopamine projections from the VTA innervate all three forebrain nuclei, the blockade of dopamine receptors only in the dPFC antagonized cocaine-induced reinstatement. Furthermore, DA administration into the dPFC was sufficient to elicit a reinstatement in drug-related responding. These data demonstrate that dopamine release in the dPFC initiates a dPFC-NAcore-VP series circuit that mediates cocaine-induced drug-seeking behavior.

Repeated cocaine treatment and withdrawal produces changes in brain function thought to be involved in relapse to drug use. Withdrawal from repeated cocaine reduced in vivo extracellular glutamate in the nucleus accumbens of rats by decreasing the exchange of extracellular cystine for intracellular glutamate. In vivo restoration of cystine/glutamate exchange by intracranial perfusion of cystine or systemically administered N-acetylcysteine normalized the levels of glutamate in cocaine-treated subjects. To determine if the reduction in nonvesicular glutamate release is a mediator of relapse, we examined cocaine-primed reinstatement of drug seeking after cocaine self-administration was stopped. Reinstatement was prevented by stimulating cystine/glutamate exchange with N-acetylcysteine and restoring extracellular glutamate. Thus, withdrawal from repeated cocaine increases susceptibility to relapse in part by reducing cystine/glutamate exchange, and restoring exchanger activity prevents cocaine-primed drug seeking.

The relative contributions of glutamate and dopamine within the nucleus accumbens to cocaine-induced reinstatement of drug-seeking behavior were assessed. When extinguished cocaine self-administration behavior was reinstated by a cocaine-priming injection, extracellular levels of both dopamine and glutamate were elevated in the nucleus accumbens. However, when yoked cocaine or saline control subjects were administered a cocaine prime, only dopamine levels were elevated. Thus, glutamate increased only when animals reinstated lever pressing, whereas dopamine increased regardless of behavior. The increase in glutamate was not accounted for simply by the act of lever pressing itself, because the cocaine self-administration group still demonstrated elevated glutamate when the levers were withdrawn from the operant chamber. Moreover, reinstatement of lever pressing for food did not elevate extracellular glutamate, indicating that increased glutamate initiated responding selectively for a drug reinforcement. The source of glutamate was shown to be glutamatergic afferents from the prefrontal cortex because inhibiting prefrontal cortical glutamatergic neurons that project to the accumbens prevented the rise in glutamate. Together, these data demonstrate that activation of a glutamatergic projection from the prefrontal cortex to the nucleus accumbens underlies cocaine-primed reinstatement of drug-seeking behavior.

The role of limbic, cortical, and striatal circuitry in a footshock reinstatement model of relapse to cocaine seeking was evaluated. Transient inhibition of the central extended amygdala [CEA; including the central nucleus of the amygdala (CN), ventral bed nucleus of the stria terminalis (BNSTv), and nucleus accumbens shell (NAshell)], ventral tegmental area (VTA), and motor circuitry [including the dorsal prefrontal cortex (PFCd), nucleus accumbens core (NAcore), and ventral pallidum (VP)] blocked the ability of footshock stress to reinstate lever pressing previously associated with cocaine delivery. However, inhibition of the basolateral amygdala, mediodorsal nucleus of the thalamus, or the ventral prefrontal cortex had no effect on drug-seeking behavior. These data suggest that footshock stress activates limbic circuitry of the CEA that, via the VTA, activates motor output circuitry responsible for producing lever press responding. Consistent with this notion, the D 1 /D 2 dopamine receptor antagonist fluphenazine blocked footshock-induced reinstatement when infused into the PFCd. Further, inhibition of the NAshell blocked a footshock-induced increase in dopamine within the PFC and concomitantly blocked reinstatement responding. Also supporting the idea of a CEA-VTA-motor circuit in stress-induced reinstatement of cocaine seeking, inactivation of the PFCd was shown to block stress-induced glutamate release within the NAcore while concurrently inhibiting reinstatement responding. Taken together, these data suggest that footshock activates limbic circuitry in the CEA, which in turn activates a VTA dopamine projection to the PFCd. The rise in dopamine within the PFCd initiates reinstatement via a glutamatergic projection to the NAcore.

Rationale: Recent studies have attempted to identify the neuroanatomical substrates underlying primed reinstatement of drug-seeking behavior. Identification of neuronal substrates will provide a logical rationale for designing pharmacological interventions in treating drug relapse. Objective: The objective was to identify brain circuitry that is shared between cue-, drugand stress-primed reinstatement, as well as identifying aspects of brain circuitry that are distinct for each stimulus modality. The resulting circuit offers theoretical interpretations for consideration in future studies. Results: Aspects of the circuitry mediating reinstatement can be identified with reasonable confidence. The role of the basolateral amygdala in cue-primed reinstatement, the role of the ventral tegmental area in drug-primed reinstatement and the role of adrenergic innervation of the extended amygdala in stress-primed reinstatement are well characterized. Also, all three modes for priming reinstatement may converge on the anterior cingulate cortex and have a final common output through the core of the nucleus accumbens. Lacunae in our understanding of the circuit were identified, especially with regard to how stress priming is conveyed from the extended amygdala to the shared anterior cingulate accumbens core circuit. Conclusions: The proposed convergence of priming stimuli into the glutamatergic projection from anterior cingulate to the accumbens core combined with the changes in glutamate transmission and signaling that accompany repeated psychostimulant administration points to the potential value of pharmacological agents that manipulate glutamate release or postsynaptic glutamate receptor signaling and trafficking in treating primed relapse in addicts.